CORE SUMMARY This Program Project Grant (PPG) is a highly integrated effort to bring together scientists with a broad spectrum of expertise to understand the role of disordered wall mechanics in esophageal disease. The PPG will test the hypothesis that esophageal disease and associated symptom severity are primarily linked to abnormalities of impaired distensibility of the esophageal wall and that this is mediated through various cellular and molecular responses in the esophageal wall and modulated by underlying visceral hypersensitivity and hypervigilance. Given this comprehensive approach, four studies have been designed that target the gamut of research science from ex-vivo studies in animal models to in-vivo studies in humans using translational physiology that will be complemented by in-silico models and in-natura assessments of patient reported outcomes. Project 1 will seek to determine the molecular mechanisms that alter distensibility of the esophageal wall. Project 2 will test the hypothesis that an altered response to volumetric distention is a crucial factor in esophageal disease. Project 3 will develop and refine in-silico models of bolus transport that focus on abnormalities in esophageal distensibility. Project 4 will quantify the interaction between bolus transport mechanics, esophageal distensibility and psychological factors in modulating esophageal symptoms (Project 4). These projects will be supported by two unique COREs; the Biophysiologic Modeling Core (CORE B) and the Biorepository and Tissue Material Characterization CORE (CORE C). The cooperation and collaboration between the four projects and the two COREs will be achieved through teamwork between the Program Project and the CORE teams and the Administrative CORE will bear the primary responsibility for coordinating these interactions through five interrelated specifics aims: Aim 1. To support communication, sharing of materials and dissemination of information between the Project Investigators, the CORE Leaders, Collaborating investigators, the Internal and External Advisory Committees and the Institutional CORES. Aim 2. To provide financial and regulatory oversight of the Project and CORE Leaders and coordinate their interactions with Institutional CORE Services. Aim 3. To coordinate data collection, data security, and analysis efforts between the Projects and COREs to monitor adherence with institutional policies, ensure patient confidentiality, and keep individual PPG Components on track with the overall PPG timeline. Aim 4. To disseminate findings of the project investigators and progress of the project COREs to other institutions and investigators and facilitate discussion of new approaches to research of esophageal wall mechanics. Aim 5. To coordinate administrative tasks such as IRB submissions and NIDDK report generation, and organize documentation to maximize PPG efficiency, as well as patient recruitment and retention.